JP7244571B2 - ワクチン接種に有用なt細胞エピトープの予測 - Google Patents
ワクチン接種に有用なt細胞エピトープの予測 Download PDFInfo
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Description
a)1つ又は複数のMHCクラスII分子への、修飾されたタンパク質の断片である修飾されたペプチドの結合のスコアを確かめる工程と、
b)修飾されたタンパク質の発現又は存在量のスコアを確かめる工程と
を含む方法に関する。
a)1つ又は複数のMHCクラスII分子への、修飾されたタンパク質の断片である修飾されたペプチドの結合のスコアを確かめる工程と、
b)修飾されたタンパク質の発現又は存在量のスコアを確かめる工程と
を含み、2つ以上の異なる修飾について工程a)及びb)を行う工程を含む方法に関する。
本発明の方法によって免疫原性又は(同様に分析された他の修飾又は修飾されたペプチドよりも)免疫原性であると予測される修飾又は修飾されたペプチドを同定する工程を含む方法に関する。一実施形態では、本方法は、
免疫原性若しくはより免疫原性であると予測される修飾若しくは修飾されたペプチドを含むペプチド若しくはポリペプチド、又はこのペプチド若しくはポリペプチドをコードする核酸を含むワクチンを提供する工程を更に含む。
(a)本発明による方法を使用してワクチンを提供する工程と、
(b)前記ワクチンを患者に投与する工程と
を含む方法に関する。
。
1)たとえば、最初にRonaghiら、1998: A sequencing method based on real-time pyrophosphate. Science 281(5375)、363~365頁に記載されている、Roche関連会社454 Life Sciences社(コネチカット州Branford)のGS-FLX 454 Genome Sequencer(商標)で実装されるパイロシーケンシングとして知られる合成技術によるシーケンシング。この技術は、エマルジョンPCR増幅のために油に取り囲まれたPCR反応物質を含有する水性ミセル中で激しく渦撹拌することによって一本鎖DNA結合ビーズがカプセル封入される、エマルジョンPCRを使用する。パイロシーケンシング工程中、ポリメラーゼがDNA鎖を合成する際にヌクレオチドの取り込み中にリン酸分子から放出される光が記録される。
2)可逆的色素-ターミネーターに基づいており、たとえばIllumina/Solexa Genome Analyzer(商標)及びIllumina HiSeq 2000 Genome Analyzer(商標)で実装されているSolexa社(現在はIllumina Inc.社の一部、カリフォルニア州San Diego)によって開発された、合成手法によるシーケンシング。この技術では、4つすべてのヌクレオチドを同時に、DNAポリメラーゼと共にフローセルチャネル中のオリゴ初回刺激したクラスター断片に加える。架橋増幅によりシーケンシングのために4つすべての蛍光標識ヌクレオチドを有するクラスター鎖を伸長させる。
3)たとえばApplied Biosystems社(現在はLife Technologies Corporation、カリフォルニア州Carlsbad)のSOLid(商標)プラットフォームで実装されている、ライゲーション手法によるシーケンシング。この技術では、固定長のすべての可能なオリゴヌクレオチドのプールを、シーケンシングした位置に従って標識する。オリゴヌクレオチドがアニーリング及びライゲーションされ、DNAリガーゼによる一致した配列の優先的なライゲーションは、その位置でのヌクレオチドの情報を与えるシグナルをもたらす。シーケンシングの前に、DNAをエマルジョンPCRによって増幅する。それぞれ同じDNA分子のコピーしか含有しない、生じるビーズをスライドガラス上に載せる。2つ目の例として、Dover Systems社(ニューハンプシャー州Salem)のPolonator(商標)G.007プラットフォームも、ランダムにアレイ配置したビーズに基づくエマルジョンPCRを使用して、並列シーケンシングのためにDNA断片を増幅することによって、ライゲーション手法によるシーケンシングを用いる。
4)たとえば、Pacific Biosciences社(カリフォルニア州Menlo Park)のPacBio RSシステム又はHelicos Biosciences社(マサチューセッツ州Cambridge)のHeliScope(商標)プラットフォームで実装されている単一分子シーケンシング技術。この技術の明確な特徴は、単一分子リアルタイム(SMRT)DNAシーケンシングと定義される、単一のDNA又はRNA分子を増幅なしにシーケンシングするその能力である。たとえば、HeliScopeは、それぞれのヌクレオチドが合成されていく最中にそれを直接検出するために、高感度の蛍光検出システムを使用する。蛍光共鳴エネルギー移動(FRET)に基づく同様の手法がVisigen Biotechnology社(テキサス州Houston)から開発されている。他の蛍光に基づく単一分子技法は、U.S.Genomics(GeneEngine(商標))及びGenovoxx(AnyGene(商標))からのものである。
5)たとえば複製中に単一鎖上のポリメラーゼ分子の動きを監視するためにチップ上に配置されている様々なナノ構造を使用する、単一分子シーケンシングのためのナノ技術。ナノ技術に基づく手法の非限定的な例は、Oxford Nanopore Technologies社(英国Oxford)のGridON(商標)プラットフォーム、Nabsys社(ロードアイランド州Providence)によって開発されたハイブリダイゼーション支援のナノポアシーケンシング(HANS(商標))プラットフォーム、及びコンビナトリアルプローブアンカーライゲーション(cPAL(商標))と呼ばれるDNAナノボール(DNB)技術を用いた商標を有するリガーゼに基づくDNAシーケンシングプラットフォームである。
6)単一分子シーケンシングのための電子顕微鏡観察に基づく技術、たとえばLightSpeed Genomics社(カリフォルニア州Sunnyvale)及びHalcyon Molecular社(カリフォルニア州Redwood City)によって開発されたもの。
7)DNAの重合中に放出される水素イオンの検出に基づくイオン半導体シーケンシング。たとえば、Ion Torrent Systems社(カリフォルニア州San Francisco)は、この生化学的プロセスを超並列の様式で行うために微小測定ウェルの高密度アレイを使用する。それぞれのウェルは異なるDNA鋳型を有する。ウェルの下にイオン感受性層があり、その下に商標を有するイオンセンサーがある。
ープが由来する抗原を発現する細胞に対するCD8+T細胞応答を誘発することができるエピトープを提供する。一実施形態では、癌特異的体細胞突然変異を含有しないエピトープは腫瘍抗原に由来する。一実施形態では、癌特異的体細胞突然変異を含有しないネオエピトープ及びエピトープは癌の処置において相乗効果を有する。好ましくは、本発明に従って提供されるワクチンは細胞毒性及び/又はヘルパーT細胞応答のポリエピトープ刺激に有用である。
材料と方法
試料。雌8~12週齢C57BL/6、BALB/cマウス(Janvier Labs社)及びC57BL/6BrdCrHsd-Tyrcマウス(B6アルビノ、Harlan社)を、マインツ大学(University of Mainz)における動物研究に関する連邦政府政策に従って維持した。B16F10メラノーマ細胞株、CT26結腸癌腫細胞株及び4T1-luc2-tdtomato(4T1-Luc)細胞は、それぞれ2010、2011及び2011年に購入し(ATCC CRL-6475ロット#58078645、ATCC CRL-2638ロット#58494154、Caliper 125669ロット#101648)、サプライヤーによって示唆される通りに維持した。ホタルルシフェラーゼ発現CT26-Luc及びB16F10-Luc細胞は、レンチウイルスにより形質導入した。マスター及び作業用細胞バンクを作製し、その3回目及び4回目の継代を腫瘍実験に使用した。
突然変異したエピトープの免疫原性を調べる実験のため、0、3、7及び14日目に(RNAによる免疫化)又は0及び7日目に(ペプチドによる免疫化)、同齢雌C57BL/6又はBALB/cマウスにワクチン接種し、最後の免疫化から5~6日後に読み取りを行った。カチオン性脂質と複合体形成した200μl(B16F10は突然変異当たり20μg、CT26は突然変異当たり40μg)RNAの後眼窩注射(投稿準備中)又はPBS中に製剤化された100μg合成ペプチド及び50μgポリ(I:C)の外側の側腹部への皮下注射(200μL総容量)のいずれかによりワクチン接種を行った。マウス当たり2種の突然変異を検査した(B16F10はn=5、CT26はn=3)。免疫原性突然変異及びサブタイプ分類の確認のため、単一突然変異に対してマウスにワクチン接種した(n=5)。
機構的研究のため、CD8枯渇(クローンYTS191、BioXcell社)、CD4枯渇(クローンYTS169.1、BioXcell社)又はCD40L遮断(クローンMR1、Stephen Schoenberger教授のご厚意により分与)抗体の反復用量を、図に示す通りに腹腔内投与した(200μL PBS中に200μg/マウス)。
ネオエピトープワクチンにおけるMHCクラスII限定T細胞エピトープ
A.突然変異したエピトープに対し反応性のT細胞サブタイプの特徴づけ
近年、本発明者らは、NGSによるB16F10腫瘍の非同義突然変異の包括的マッピングのためのワークフローについて記載した(図1a)(Castle, J. C.ら、Cancer Res 72、1081 (2012))。腫瘍を有するC57BL/6マウスを、突然変異したエピトープ(位置14に突然変異)をコードする合成27merペプチドで免疫化し、in vivo腫瘍制御を付与するT細胞応答をもたらした。この研究の継続において、本発明者らは次に、MHC I結合の高い見込みを有するものから始めて、突然変異したエピトープに対するT細胞応答を特徴づけた。マウスに合成27merの突然変異したエピトープペプチドをワクチン接種した(図1b右上)。IFN-γ ELISpotにおいてマウスの脾細胞を検査して、サブタイプ及びサイトカイン発現のさらなる分析のための免疫原性突然変異を同定した(図1a)。突然変異したエピトープの約30%は、マウスにおいて突然変異反応性サイトカイン分泌T細胞を誘導することが判明した(図1b)。驚いたことに、殆ど全ての突然変異したエピトープ(16/17、95%)に対する応答は、CD4+T細胞型のものであった(図1b、Table 1(表1))。
MHCクラスII限定癌突然変異が、in vivoにおける優れたワクチン標的であるか調べるために、本発明者らは、ワクチンフォーマットとしての合成RNAの使用へと進んだ。抗原コード合成RNAは、2つ以上のエピトープを送達するその能力、抗原提示細胞(APC)によるその選択的な取込み、及びその固有のアジュバント活性を含むその利点により、有望なワクチン技術として現れつつある(Diken, M.ら、Gene Ther 18、702 (2011);Kreiter, S.ら、Curr Opin Immunol 23、399 (2011);Pascolo, S.、Handb Exp Pharmacol、221 (2008);Sahin, U.ら、Nat Rev Drug Discov 13、759 (2014);Van, L. S.ら、Hum Vaccin Immunother 9(2013))。本発明者らのグループは、薬理学的に最適化されたRNA(RNA配列及びリポソーム製剤における安定化エレメント)を開発し、これはその一方で、臨床検査(NCT01684241)の段階に達した(Holtkamp, S.ら、Blood 108、4009 (2006);Kreiter, S.ら、J Immunol 180、309 (2008);Kuhn, A. N.ら、Gene Ther 17、961 (2010))。本発明者らは、B16F10腫瘍モデルにおいて同定されたエピトープの1つであるB16-M30をコードするRNAを遺伝子操作した。B16-M30は、野生型ペプチドを認識しない強いCD4+T細胞応答を誘発した(図2a左)が、このことは、突然変異したアミノ酸が、T細胞認識に必須であると示されたことから分かる(図2a右)。B16F10腫瘍を有するC57BL/6マウスに、B16-Mt30 RNAモノトープを反復的にワクチン接種した場合、腫瘍成長は大いに遅延された(図2b)。B16-M30 RNA処置マウスの半分が、腫瘍ワクチン接種の120日後に未だ生きていたが、対照RNA処置マウスは全て、65日以内に死んだ。
重大な問題の1つは、効率的抗腫瘍免疫の誘導の最高確率を有する突然変異をどのように選択するかである。本発明者ら(図1d右)及び他の研究者ら(Matsushita, H.ら、Nature 482、400 (2012);Robbins, P. F.ら、Nat Med 19、747 (2013);van, R. N.ら、J Clin Oncol 31、e439-e442 (2013))は、MHCクラスI結合スコアが、CD8+応答及び腫瘍拒絶を誘発する突然変異したエピトープ候補の濃縮を可能にすることを示した(Duan, F.ら、J Exp Med 211、2231 (2014))。上述の本発明者らの知見は、MHCクラスII提示の突然変異したエピトープが、MERITアプローチの更に高い関心の的になることも可能であることを示す。実際、相関分析は、免疫原性突然変異が、非免疫原性のものと比較して有意により良いMHCクラスII結合スコアを有することを明らかにした(図4a)。大部分の癌は、MHCクラスII発現を欠く。MHCクラスII陰性腫瘍におけるCD4+T細胞によるネオエピトープの有効な認識は、抗原提示細胞(APC)によって取り入れられて提示されることになる腫瘍抗原の放出に依存する筈である。これは、高度に豊富な発現を有する抗原に最も効率的となる筈である。この仮説を検査するために、本発明者らは、優れたMHCクラスII結合を、突然変異したエピトープをコードするmRNAの豊富な発現と組み合わせたアルゴリズムを実行した。後者のため、本発明者らは、全体的な読み取りデータ計数に対して正規化された、確認された突然変異したRNAシーケンシング読み取りデータを使用した(NVRC:正規化された変異体読み取りデータ計数)。本発明者らは、このアルゴリズムによりCT26ミュータノームデータをランクづけし、最も豊富な候補エピトープ(NVRC≧60)の間から、優れたMHCクラスII結合剤であると予測される上位10種の突然変異を選択した(Table 4(表4)における「ME」突然変異)。対照として、本発明者らは、豊富な発現のみに基づき10種の突然変異を選択する(Table 4(表4)における「E」突然変異)。最も重要なことに、これらのエピトープを、さらなる予備検証又は免疫原性検査を全く行わずに使用して、群毎に2種のRNAペンタトープを遺伝子操作した(PME及びPEペンタトープ)。確立されたCT26-Luc肺腫瘍を有するマウスにこれらのエピトープをワクチン接種した場合、PMEは、PEペンタトープと比較して、はるかにより強いT細胞応答を誘導した(図4c)。確立された肺転移は、ほぼ全てのマウスにおいて完全に拒絶された一方、PEペンタトープは、腫瘍成長制御を付与することができなかった(図4b)。
要約すると、本発明者らのデータは、MHCクラスII限定T細胞エピトープが、癌ミュータノームにおいて豊富であり、マウス腫瘍モデルにおいて実質的な治療効果を有するRNAに基づくポリネオエピトープワクチンのカスタマイズに使用することができることを示す。
抗腫瘍免疫を有する突然変異の選択
アミノ酸配列修飾の選択/ランクづけのため、次の通りに進むことができる:
1.非同義点突然変異の所定のリスト内で、中央に突然変異したアミノ酸を有し、それぞれN及びC末端において最大13アミノ酸に両側を挟まれたペプチド配列を算出する;この配列は、以下の文では27merと呼ばれる(突然変異が、タンパク質全体のN又はC末端に近い場合、各両側フランキング配列の長さは、13アミノ酸より小さくてもよい)
2.各27merの重複する15nt長の部分列毎に、MHCクラスII結合予測コンセンサススコアを算出する(例えば、IEDB T細胞予測ツール[Wang Pら、(2010) BMC Bioinformatics. 11:568. PMID: 21092157. http://tools.immuneepitope.org/mhcii/]を使用して);最良(=最低)スコアが27mer全体に割り当てられる
3.27merが関連する遺伝子の発現(好ましくは、RPKM単位で[Ali Mortazaviら、(2008) Nature Methods 5、621~628])を算出する
4.RNAにおける各突然変異の変異体対立遺伝子頻度(VAF)を算出する:
- 入力は、突然変異検出に使用されたものと同じ腫瘍試料により為されたRNA-Seq実験の短い読み取りデータ整列である
- 突然変異部位に重複する整列及び読み取りデータを探索する
- 先の工程で集計された読み取りデータを使用して、突然変異部位にマッピングされるヌクレオチドを符合させる
- 突然変異のゲノム部位にマッピングされる全ヌクレオチドの合計で割った突然変異体対立遺伝子ヌクレオチドの合計を算出する(図5)
5.それぞれの遺伝子発現にVAFを掛けて、突然変異発現を得る(好ましくは、RPKM単位で)
6.MHC結合スコア(工程2において算出され、最低スコアが最良である)によって全27merをランクづけし、所定の閾値未満の関連する突然変異発現を有する27merを除去する
アルゴリズムを検査するため、マウス腫瘍モデル4T1、CT26及びB16F10から185種の突然変異を選択し、その抗原性について検査した。次に、本発明者らは先ず、アルゴリズムの予測性能における遺伝子及び突然変異発現のレベルの影響の検査を試みた(図6)。そこで、本発明者らは、遺伝子発現の代わりに突然変異発現にフィルターをかけた場合、受信者動作特性の最大曲線下面積(ROC AUC [Fawcett T.、Pattern Recogn Lett. 2006;27:861~874. doi: 10.1016/j.patrec.2005.10.010])が、より高いことを観察することができる(図6左(遺伝子発現)vs.右(突然変異発現)プロット)。
図7は、ごく並の相対的結合親和性を有する結合剤の突然変異発現の顕著な影響を示す、最適閾値のROC曲線を示す(図7、右パネル、偽陽性率約0.3~0.6の間の値)。
Claims (24)
- アミノ酸修飾の免疫原性を予測するための方法であって、
a)1つ又は複数のMHCクラスII分子への、修飾されたタンパク質の断片を含む修飾されたペプチドの結合のスコアを確かめる工程と、
b)修飾されたタンパク質の発現又は存在量のスコアを確かめる工程であって、修飾されたタンパク質の発現又は存在量のスコアを確かめる工程が、修飾が関連するタンパク質の発現のレベルを決定する工程と、修飾が関連するタンパク質の間での修飾されたタンパク質の頻度を決定する工程とを含み、修飾が関連するタンパク質の間での修飾されたタンパク質の頻度が、変異体対立遺伝子頻度を決定することにより決定される工程と、
c)以下を含む1つ又は複数の要因に基づいて、前記アミノ酸修飾の免疫原性を予測する工程:
(i)修飾されたペプチドの1つまたは複数のMHCクラスII分子への結合のスコアが結合を示すかどうか、及び
(ii)修飾されたペプチドの発現又は存在量のスコアが発現または存在量を示すかどうか
を含み、対応する修飾されたタンパク質の発現又は存在量がより高いペプチドは、対応する修飾されたタンパク質の発現または存在量がより低いペプチドよりも良好にスコアづけされる、方法。 - 1つ又は複数のMHCクラスII分子への結合を示す1つ又は複数のMHCクラスII分子への結合のスコアと、修飾されたタンパク質の発現、所定の閾値を満たすあるレベルの発現又は存在量を示す修飾されたタンパク質の発現又は存在量のスコアが、修飾又は修飾されたペプチドが免疫原性であることを示す、請求項1に記載の方法。
- 免疫原性アミノ酸修飾を選択及び/又はランクづけするための方法であって、
a)1つ又は複数のMHCクラスII分子への、修飾されたタンパク質の断片である修飾されたペプチドの結合のスコアを確かめる工程と、
b)修飾されたタンパク質の発現又は存在量のスコアを確かめる工程であって、2つ以上の異なる修飾について工程a)及びb)を行うことを含み、修飾されたタンパク質の発現又は存在量のスコアを確かめる工程が、修飾が関連するタンパク質の発現のレベルを決定する工程と、修飾が関連するタンパク質の間での修飾されたタンパク質の頻度を決定する工程とを含み、修飾が関連するタンパク質の間での修飾されたタンパク質の頻度が、変異体対立遺伝子頻度を決定することにより決定される工程と、
c)以下を含む1つ又は複数の要因に基づいて、前記修飾されたペプチドを免疫原性またはより免疫原性であると同定する工程:
(i)修飾されたペプチドの1つまたは複数のMHCクラスII分子への結合のスコアが結合を示すかどうか、及び
(ii)修飾されたペプチドの発現又は存在量のスコアが発現または存在量を示すかどうか
を含み、対応する修飾されたタンパク質の発現又は存在量がより高いペプチドは、対応する修飾されたタンパク質の発現または存在量がより低いペプチドよりも良好にスコア付けされる、方法。 - 前記2つ以上の異なる修飾のスコアを比較する工程を含む、請求項3に記載の方法。
- 前記2つ以上の異なる修飾のスコアが、異なる修飾をそれらのMHCクラスII結合スコアによってランクづけし、所定の閾値未満の発現又は存在量を有する修飾を除去することにより比較される、請求項3又は4に記載の方法。
- 1つ又は複数のMHCクラスII分子への結合のスコアが、1つ又は複数のMHCクラスII分子への結合の確率を反映する、請求項1から5のいずれか一項に記載の方法。
- 2つ以上の異なる修飾されたペプチドについて工程a)を行う工程を含み、前記2つ以上の異なる修飾されたペプチドが同じ修飾を含む、請求項1から6のいずれか一項に記載の方法。
- 同じ修飾を含む2つ以上の異なる修飾されたペプチドが、修飾されたタンパク質の異なる断片を含み、前記異なる断片が、タンパク質に存在する同じ修飾を含む、請求項7に記載の方法。
- 同じ修飾を含む2つ以上の異なる修飾されたペプチドが、修飾されたタンパク質の異なる潜在的MHCクラスII結合断片を含み、前記断片が、タンパク質に存在する同じ修飾を含む、請求項7又は8に記載の方法。
- 1つ又は複数のMHCクラスII分子への結合の確率又は最高確率を有する、同じ修飾を含む2つ以上の異なる修飾されたペプチドから修飾されたペプチドを選択する工程を更に含む、請求項7から9のいずれか一項に記載の方法。
- 同じ修飾を含む2つ以上の異なる修飾されたペプチドが、(a)ペプチドの長さ及び/又は(b)ペプチド内の修飾の位置が異なる、請求項7から10のいずれか一項に記載の方法。
- 同じ修飾を含む2つ以上の異なる修飾されたペプチドの1つ又は複数のMHCクラスII分子への結合の最良スコアが、修飾に割り当てられる、請求項7から11のいずれか一項に記載の方法。
- 前記修飾が関連するタンパク質の発現のレベルを決定する工程及び/又は修飾が関連するタンパク質の間での修飾されたタンパク質の頻度を決定する工程が、RNAレベルで行われる、請求項1から12のいずれか一項に記載の方法。
- 変異体対立遺伝子頻度が、突然変異部位をカバーする全ての検出された配列の合計で割った、突然変異部位をカバーし、突然変異を保有する検出された配列の合計である、請求項1から13のいずれか一項に記載の方法。
- 修飾されたタンパク質の発現又は存在量のスコアを確かめるために、修飾が関連するタンパク質の発現のレベルのスコアに、修飾が関連するタンパク質の間での修飾されたタンパク質の頻度のスコアを掛ける、請求項1から14のいずれか一項に記載の方法。
- 修飾されたペプチドが、修飾されたタンパク質の断片を含み、前記断片が、タンパク質に存在する修飾を含む、請求項1から15のいずれか一項に記載の方法。
- 1つ又は複数のタンパク質コード領域における非同義突然変異を同定する工程を更に含む、請求項1から16のいずれか一項に記載の方法。
- アミノ酸修飾が、1個又は複数の細胞のゲノム又はトランスクリプトームを部分的に又は完全にシーケンシングし、1つ又は複数のタンパク質コード領域における突然変異を同定することによって同定される、請求項1から17のいずれか一項に記載の方法。
- 前記突然変異が、体細胞突然変異である、請求項17又は18に記載の方法。
- 前記突然変異が、癌突然変異である、請求項17から19のいずれか一項に記載の方法。
- ワクチンの製造において使用される、請求項1から20のいずれか一項に記載の方法。
- ワクチンが、
(a) 請求項1、2及び6から20のいずれか一項に記載の方法により、免疫原性又はより免疫原性であると予測された1つ又は複数の修飾又は修飾されたペプチド;あるいは
(b) 請求項3から20のいずれか一項に記載の方法により、選択及び/又はランクづけされた1つ又は複数の免疫原性修飾又は修飾されたペプチド
に由来する、請求項21に記載の方法。 - ワクチンを提供するための方法であって、
(a) 請求項1、2及び6から20のいずれか一項に記載の方法により、免疫原性又はより免疫原性であると予測された1つ又は複数の修飾又は修飾されたペプチド;あるいは
(b) 請求項3から20のいずれか一項に記載の方法により、選択及び/又はランクづけされた1つ又は複数の免疫原性修飾又は修飾されたペプチド
を同定する工程を含む方法。 - (a)前記免疫原性又はより免疫原性であると予測された1つ又は複数の修飾又は修飾されたペプチド;あるいは(b)前記選択及び/又はランクづけされた1つ又は複数の免疫原性修飾又は修飾されたペプチドを含むペプチド若しくはポリペプチド、又は前記ペプチド若しくはポリペプチドをコードする核酸を含むワクチンを提供する工程
を更に含む、請求項23に記載の方法。
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